Primary effusion lymphoma (PEL) is an aggressive type of non-Hodgkin lymphoma localized predominantly in body cavities and occasionally in extracavitary regions (Patel and Xiao, 2013). Kaposi's sarcoma associated herpesvirus (KSHV) is the causative agent for PEL (Cesarman et al., 1995) and this disease primarily occurs in patients with human immunodeficiency virus (HIV) infection and severe immunodeficiency (Patel and Xiao, 2013). However, it can also occur in HIV negative individuals who are immunocompromised as a result of solid-organ transplantation (Riva et al., 2012) and very rarely in elderly population. The prognosis of PEL is very poor with a median survival of 4 and 6 months in HIV positive and negative patients, respectively (Kobayashi et al., 2007). Although administration of cytotoxic chemotherapeutic agents represents the current standard of care (Riva et al., 2012). Impaired clinical condition and severe immunodeficiency enhanced the chemotherapy toxicity and increased the risk of treatment-related mortality (Boulanger et al., 2005). At present there is no standard treatment available for PEL and it remains an incurable malignancy. Thus there is an urgent need to develop new treatment regimens for PEL.
Interferon regulatory factor 4 (IRF4), a transcription factor expressed in cells of the immune system, is an essential regulator at multiple steps in B-Cell differentiation and is associated with many lymphoid malignancies (Shaffer et al., 2009). It has been shown that 100% of PEL cases express IRF-4 and its expression was a selective feature of PEL among lymphomas involving the serous body cavities as secondary lymphomatous effusions generally failed to express this protein (Carbone et al., 2000). Lenalidomide and pomalidomide which are derived from the parent compound thalidomide (all of them FDA approved) are collectively referred to as immunomodulatory drugs (IMiDs). Both lenalidomide and pomalidomide demonstrated more potent anti-myeloma, anti-inflammatory and immunomodulatory activities than thalidomide (Zhu et al., 2013). The anti-myeloma activity of IMiDs is mediated via both direct and indirect mechanisms. As their name implies these drugs modulate the immune activity by enhancing the CD4+ and CD8+ T cell co-stimulation and they are also potent inducers of T cell proliferation and enhance the production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) (Zhu et al., 2013). It has been recently found that the direct cellular targets of IMiDs are Cereblon (CRBN) (Ito et al., 2010), Ikaros family zinc finger-1 (IKZF1/IKAROS), Ikaros family zinc finger-3 (IKZF3/AIOLOS) (Kronke et al., 2014; Lu et al., 2014) and Interferon regulatory factor-4 (IRF-4) (Yang et al., 2012). Since, IRF-4 is expressed in all PEL cases we hypothesized that targeting IRF-4 in PEL by IMiDs would be effective against this disease. We found that IMiDs lenalidomide and pomalidomide at physiologically achievable concentrations are efficacious and selective against PEL in a panel of cell lines tested. Further, we discovered that shRNA mediated knockdown of MYC enhanced the anti-proliferative potential of IMiDs in PEL and low dose combinations of IMiDs with bromodomain-containing protein 4 (BRD4) inhibitors (which directly inhibit MYC transcription) displayed synergistic anti-proliferative potential against PEL.